VHL loss of function and its impact on oncogenic signaling networks in clear cell renal cell carcinoma.
Loss of von Hippel-Lindau tumor suppressor gene function occurs in familial and most sporadic clear cell renal cell carcinoma, resulting in the aberrant expression of genes that control cell proliferation, metabolism, invasion and angiogenesis. The molecular mechanisms by which loss of function leads to tumorigenesis are not yet fully defined. The von Hippel-Lindau gene product is part of an ubiquitin ligase complex that targets hypoxia inducible factors for polyubiquitination and proteasomal degradation, linking hypoxia response genes to renal cell carcinoma oncogenesis. Loss von Hippel-Lindau gene function also promotes cell invasiveness in response to hepatocyte growth factor, an important regulator of kidney development and renal homeostasis. Increased cell invasiveness is mediated by another ubiquitin ligase target with relevance to the molecular pathogenesis of renal cell carcinoma: beta-catenin. This discovery and other recent insights into kidney cancer oncogenesis implicate convergent developmental and homeostatic signaling pathways in tumorigenesis, tumor invasiveness and metastasis.
Linehan
W Marston
WM
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Rubin
Jeffrey S
JS
Bottaro
Donald P
DP
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D051176:beta Catenin; D051794:Von Hippel-Lindau Tumor Suppressor Protein